Increased or decreased mechanical strain results in changes in bone mass. Osteocytes appear to be the cells that sense changes in strain and release biologic signaling molecules that either increase bone resorption, maintain bone mass or increase bone formation. The rations of bone resorbing signals to bone forming signals released by the osteocyte determine if bone mass is increased, decreased or remains unchanged. During microdamage of bone, this signaling system may be amplified due to the accelerated release of bone resorbing signals from apoptotic osteocytes. The long-range goal of this proposal is to understand how osteocytes change bone mass in response to mechanical strain and the short-range goal is to determine how osteocytes induce osteoclast formation. Our hypothesis is that one of the means whereby osteocytes regulate bone mass is through stimulating the formation and activation of osteoclasts. The specific aims on this proposal are 1) to examine the mechanism whereby osteocytes support osteoclast formation, 2) to determine the effects of mechanical strain on the process, 3) to determine if bone anabolic agents will block or attenuate the release of osteoclast activating factors by osteocytes and 4) to determine physically stressed or dying osteocytes support osteoclast formation. It is expected that this work will increase our knowledge concerning the mechanisms whereby osteocytes can signal bone resorption. The mechanisms whereby osteocytes, in an absence of mechanical strain, can induce osteoclast formation may be the same, similar or different from the mechanism whereby physically stressed or dying osteocytes induce osteoclast formation. When these mechanisms are identified and characterized, the means to prevent bone loss due to immobilization, as suffered by hospitalized patients and the elderly, may be prevent bone loss due to immobilization, as suffered by hospitalized patients and the elderly, may be prevented or attenuated. Understanding how these signals are regulated by mechanical strain will be of additional significance for the application of specific strain regimens to maintain or increase bone mass.